Study partner profile effects on CDR-SB change in anti-amyloid therapy evaluation
INTRODUCTION: The Clinical Dementia Rating Sum of Boxes (CDR-SB), a primary outcome in anti-amyloid therapy (AAT) trials, integrates information from participants and study partners. CDR-SB scores may vary by study partner characteristics, but their impact on 18-month change interpretation remains unclear. METHODS: Using the NACC Uniform Data Set, we fitted linear mixed-effects calibration models in an Alzheimer's disease (AD)-primary early symptomatic cohort and propagated study partner-associated coefficients through Monte Carlo simulations. We estimated components of 18-month CDR-SB change under observed profile changes, simulated follow-up imbalance in a common female living-with profile, and tipping-point scenarios. Analyses were repeated in amyloid-positive and trial-like cohorts. RESULTS: The AD-primary cohort included 15,061 participants and 7,683 baseline-to-18-month pairs. Observed profile changes generated a negligible cohort-level component (mean 0.0014 points, 95% simulation interval 0.0006 to 0.0022). Simulated follow-up imbalance generated differences of 0.014 to 0.071 points across 10% to 50% reassignment. Under the primary calibration model, generating a 0.45-point difference, equal to the reported Clarity AD CDR-SB group difference, required median net imbalance >100% and was feasible in 48% of iterations. Amyloid-positive and trial-like cohorts had lower median tipping points but wider intervals, reflecting coefficient imprecision. DISCUSSION: In the large AD-primary cohort, observed study partner profile changes and simulated follow-up imbalance generated CDR-SB differences that were small relative to the 0.45-point Clarity AD benchmark. Biomarker-confirmed estimates were less stable because of coefficient imprecision. These findings suggest limited impact under typical AD-primary conditions but support systematic study partner profile collection and sensitivity analyses in observational and external-comparator CDR-SB studies for AAT evaluation.